.alpha.-Methyldopamine derivatives. Synthesis and pharmacology

Borgman, Robert J.; Baylor, Michael; McPhillips, Joseph J.; Stitzel, Robert E.

doi:10.1021/jm00250a012

Cited by 22 publications

(17 citation statements)

References 6 publications

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“…N-Me-␣-MeDA and ␣-MeDA were prepared following the procedure of Borgman et al (1974), starting from the corresponding benzaldehyde and nitroethane. 5-(GSH)-␣-MeDA was prepared according to previously published methods (Hiramatsu et al, 1990;Miller et al, 1995) with modifications as reported below.…”

Section: Methodsmentioning

confidence: 99%

Neurotoxicity of Ecstasy Metabolites in Rat Cortical Neurons, and Influence of Hyperthermia

Capela¹,

Meisel²,

Abreu³

et al. 2005

J Pharmacol Exp Ther

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3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") is a widely abused, psychoactive recreational drug. There is growing evidence that the MDMA neurotoxic profile may be highly dependent on both its hepatic metabolism and body temperature. Metabolism of MDMA involves N-demethylation to 3,4-methylenedioxyamphetamine (MDA), which is also a drug of abuse. MDMA and MDA are O-demethylenated to N-methyl-␣-methyldopamine (N-Me-␣-MeDA) and ␣-methyldopamine (␣-MeDA), respectively, both of which are catechols that can undergo oxidation to the corresponding ortho-quinones. In the presence of glutathione (GSH), ortho-quinones may be conjugated with GSH to form glutathionyl adducts. In this study, we evaluated the neurotoxicity of MDMA and three of its metabolites obtained by synthesis, N-Me-␣-MeDA, ␣-MeDA, and 5-(GSH)-␣-MeDA [5-(glutathion-S-yl)-␣-methyldopamine] in rat cortical neuronal serum-free cultures under normal (36.5°C) and hyperthermic (40°C) conditions. Cell viability was assessed, and the mechanism of cell death was also evaluated. Our study shows that these metabolites are more neurotoxic [5-(GSH)-␣-MeDA being the most toxic] than the parent compound MDMA. The neurotoxicity of MDMA metabolites was partially prevented by the antioxidants N-acetylcystein and also, in a minor extent, by ␣-phenyl-N-tert-butyl nitrone. All the tested compounds induced apoptotic cell death in cortical neurons, and their neurotoxic effect was potentiated under hyperthermic conditions. These data suggest that MDMA metabolites, especially under hyperthermic conditions, contribute to MDMA-induced neurotoxicity.

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Section: Methodsmentioning

confidence: 99%

Neurotoxicity of Ecstasy Metabolites in Rat Cortical Neurons, and Influence of Hyperthermia

Capela¹,

Meisel²,

Abreu³

et al. 2005

J Pharmacol Exp Ther

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“…The obtained salts were purified and fully characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS) methodologies. Synthesis of N-Me-a-Me-DA (HBr salt) and a-MeDA (HBr salt) was conducted according to the procedure of Borgman et al (1974), at REQUIMTE/CQFB, Chemistry Department, Faculty of Science and Technology, Universidade Nova de Lisboa, as described by Capela et al (2006).…”

Section: Test Drugsmentioning

confidence: 99%

Mixtures of 3,4-methylenedioxymethamphetamine (ecstasy) and its major human metabolites act additively to induce significant toxicity to liver cells when combined at low, non-cytotoxic concentrations

Silva

Carvalho

et al. 2013

J. Appl. Toxicol.

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Hepatic injury after 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) intoxications is highly unpredictable and does not seem to correlate with either dosage or frequency of use. The mechanisms involved include the drug metabolic bioactivation and the hyperthermic state of the liver triggered by its thermogenic action and exacerbated by the environmental circumstances of abuse at hot and crowded venues. We became interested in understanding the interaction between ecstasy and its metabolites generated in vivo as users are always exposed to mixtures of parent drug and metabolites. With this purpose, Hep G2 cells were incubated with MDMA and its main human metabolites methylenedioxyamphetamine (MDA), α-methyldopamine (α-MeDA) and N-methyl-α-methyldopamine (N-Me-α-MeDA), individually and in mixture (drugs combined in proportion to their individual EC01 ), at normal (37 °C) and hyperthermic (40.5 °C) conditions. After 48 h, viability was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Extensive concentration-response analysis was performed with single drugs and the parameters of the individual non-linear logit fits were used to predict joint effects using the well-founded models of concentration addition (CA) and independent action (IA). Experimental testing revealed that mixture effects on cell viability conformed to CA, for both temperature settings. Additionally, substantial combination effects were attained even when each substance was present at concentrations that individually produced unnoticeable effects. Hyperthermic incubations dramatically increased the toxicity of the tested drug and metabolites, both individually and combined. These outcomes suggest that MDMA metabolism has hazard implications to liver cells even when metabolites are found in low concentrations, as they contribute additively to the overall toxic effect of MDMA.

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“…N-Me-α-MeDA.HBr and α-MeDA.HBr were prepared following the procedures of Borgman 22) and Pizarro 23) starting from the corresponding benzaldehyde and nitroethane.…”

Section: Chemical Synthesismentioning

confidence: 99%

“…Hydrobromide salts of N-Me-α-MeDA (3) and α-MeDA (4) were prepared following the procedure of Borgman 22) and Pizarro 23) starting from the corresponding benzaldehyde and nitroethane. Their conjugate adducts with the bionucleophiles, GSH and NAC, 5-(GSH)-α-MeDA (7), 5-(GSH)-N-Me-α-MeDA (8), 5-(NAC)-α-MeDA (9), 5-(NAC)-N-Me-α-MeDA (10), were prepared by enzymatic oxidation according to previously published methods 26,27) with modifications.…”

Section: Chemical Synthesismentioning

confidence: 99%

Synthesis and Cyclic Voltammetry Studies of 3,4-Methylenedioxymethamphetamine (MDMA) Human Metabolites

Macedo

Branco

Ferreira

et al. 2007

JOURNAL OF HEALTH SCIENCE

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3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") is a widely abused, psychoactive recreational drug. There are growing evidences that the MDMA neurotoxic profile may be highly dependent on its hepatic metabolism. MDMA metabolism leads to the production of highly reactive derivates, namely catechols, catechol thioethers, and quinones. In this study the electrochemical oxidation-reduction processes of MDMA human metabolites, obtained by chemical synthesis, were evaluated by cyclic voltammetry based on an electrochemical cell with a glassy carbon working electrode. The toxicity of α-methyldopamine (α-MeDA), N-methyl-α-methyldopamine (N-Me-α-MeDA) and 5-(glutathion-S-yl)-α-methyldopamine [5-(GSH)-α-MeDA] to rat cortical neurons was then correlated with their redox potential. The obtained data demonstrated that the lower oxidation potential observed for the catecholic thioether of α-MeDA correlated with the higher toxicity of this adduct. This accounts for the use of voltammetry data in predicting the toxicity of MDMA metabolites.

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.alpha.-Methyldopamine derivatives. Synthesis and pharmacology

Cited by 22 publications

References 6 publications

Neurotoxicity of Ecstasy Metabolites in Rat Cortical Neurons, and Influence of Hyperthermia

Neurotoxicity of Ecstasy Metabolites in Rat Cortical Neurons, and Influence of Hyperthermia

Mixtures of 3,4-methylenedioxymethamphetamine (ecstasy) and its major human metabolites act additively to induce significant toxicity to liver cells when combined at low, non-cytotoxic concentrations

Synthesis and Cyclic Voltammetry Studies of 3,4-Methylenedioxymethamphetamine (MDMA) Human Metabolites

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